Abstract:

Hepatocellular carcinoma (HCC), considered to be one of the most lethal cancers with almost >1 million deaths
reported annually worldwide, remains a devastating disease with no known effective cure. Hence, chemopreventive
strategies come into play, offering an effective and safe mode of treatment, ideal to ward off potential cancer risks and
mortality. A major predisposing condition, pertinent to the development and progression of HCC is oxidative stress. We
previously reported a striking chemopreventive effect of anthocyanin-rich black currant skin extract (BCSE) against
diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats. The current study aims to elucidate the underlying
antioxidant mechanisms of black currant anthocyanins implicated in the previously observed chemopreventive effects
against experimental hepatocarcinogenesis. Dietary BCSE (100 and 500 mg/kg) administered four weeks before and 18
weeks after DENA challenge decreased abnormal lipid peroxidation, protein oxidation, and expression of inducible
nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in a dose-responsive fashion. Mechanistic studies revealed
that BCSE upregulated the gene expression of a number of hepatic antioxidant and carcinogen detoxifying enzymes,
such as NAD(P)H:quinone oxidoreductase, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase
isoenzymes, in DENA-initiated animals. Protein and mRNA expressions of nuclear factor E2-related factor 2 (Nrf2) were
substantially elevated with BCSE treatment, providing a direct evidence of a coordinated activation of the Nrf2-regulated
antioxidant pathway, which led to the upregulation of a variety of housekeeping genes. The results of our study provide
substantial evidence that black currant bioactive anthocyanins exert chemopreventive actions against DENA-inflicted
hepatocarcinogenesis by attenuating oxidative stress through activation of Nrf2 signaling pathway.

Abstract:Hepatocellular carcinoma (HCC), considered to be one of the most lethal cancers with almost >1 million deaths
reported annually worldwide, remains a devastating disease with no known effective cure. Hence, chemopreventive
strategies come into play, offering an effective and safe mode of treatment, ideal to ward off potential cancer risks and
mortality. A major predisposing condition, pertinent to the development and progression of HCC is oxidative stress. We
previously reported a striking chemopreventive effect of anthocyanin-rich black currant skin extract (BCSE) against
diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats. The current study aims to elucidate the underlying
antioxidant mechanisms of black currant anthocyanins implicated in the previously observed chemopreventive effects
against experimental hepatocarcinogenesis. Dietary BCSE (100 and 500 mg/kg) administered four weeks before and 18
weeks after DENA challenge decreased abnormal lipid peroxidation, protein oxidation, and expression of inducible
nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in a dose-responsive fashion. Mechanistic studies revealed
that BCSE upregulated the gene expression of a number of hepatic antioxidant and carcinogen detoxifying enzymes,
such as NAD(P)H:quinone oxidoreductase, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase
isoenzymes, in DENA-initiated animals. Protein and mRNA expressions of nuclear factor E2-related factor 2 (Nrf2) were
substantially elevated with BCSE treatment, providing a direct evidence of a coordinated activation of the Nrf2-regulated
antioxidant pathway, which led to the upregulation of a variety of housekeeping genes. The results of our study provide
substantial evidence that black currant bioactive anthocyanins exert chemopreventive actions against DENA-inflicted
hepatocarcinogenesis by attenuating oxidative stress through activation of Nrf2 signaling pathway.